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Dysfunctional Mechanotransduction Through the YAP/TAZ/Hippo Pathway As a Feature of Chronic Disease

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Dysfunctional Mechanotransduction Through the YAP/TAZ/Hippo Pathway As a Feature of Chronic Disease cells Review Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease 1, 2, 2,3, 4 Mathias Cobbaut y, Simge Karagil y, Lucrezia Bruno y, Maria Del Carmen Diaz de la Loza , Francesca E Mackenzie 3, Michael Stolinski 2 and Ahmed Elbediwy 2,* 1 Protein Phosphorylation Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] 2 Department of Biomolecular Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] (S.K.); [email protected] (L.B.); [email protected] (M.S.) 3 Department of Chemical and Pharmaceutical Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] 4 Epithelial Biology Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] * Correspondence: [email protected] These authors contribute equally to this work. y Received: 30 November 2019; Accepted: 4 January 2020; Published: 8 January 2020 Abstract: In order to ascertain their external environment, cells and tissues have the capability to sense and process a variety of stresses, including stretching and compression forces. These mechanical forces, as experienced by cells and tissues, are then converted into biochemical signals within the cell, leading to a number of cellular mechanisms being activated, including proliferation, differentiation and migration. If the conversion of mechanical cues into biochemical signals is perturbed in any way, then this can be potentially implicated in chronic disease development and processes such as neurological disorders, cancer and obesity. This review will focus on how the interplay between mechanotransduction, cellular structure, metabolism and signalling cascades led by the Hippo-YAP/TAZ axis can lead to a number of chronic diseases and suggest how we can target various pathways in order to design therapeutic targets for these debilitating diseases and conditions. Keywords: Hippo; YAP; TAZ; polarity; cancer; mechanotransduction; obesity; aPKC; neurodegenerative disease; talin; integrins 1. Mechanotransduction: Overview and Structural Basis The ability of cells to detect and react to changes in their microenvironment is critical for the maintenance of both cellular function and tissue homeostasis [1,2]. Recent studies have expanded our understanding of a cell’s ability to sense its physical surroundings and respond to these stimuli to initiate the activation of intracellular signalling pathways that trigger downstream events [1,3]. Indeed, living cells are constantly in contact with mechanical cues and can translate the mechanical forces experienced in their environment into biochemical and behavioral responses. Cells can react to these forces through specific basal proteins and transduce this into a process known as mechanotransduction [2,4,5]. Mechanotransduction is a process initiated by mechanically induced changes in protein conformation which result in cytoskeleton rearrangements, cell division control and differentiation. The mechanical forces experienced by the cell are processed into biochemical signals to ultimately control gene expression, cell shape and cell fate [6]. The cell’s response to mechanical cues within the environment requires the cell’s ability to both transmit and generate forces. This occurs through basal interactions with the cellular extracellular matrix (ECM) and cell-cell interactions with neighbouring cells through specialized transmembrane proteins [1,2]. Mechanotransduction is crucial for many cellular functions Cells 2020, 9, 151; doi:10.3390/cells9010151 www.mdpi.com/journal/cells Cells 2020, 9, 151 2 of 17 such as cell adhesion, motility, migration, proliferation, differentiation and survival. If abnormalities in mechanotransduction occur this can for example lead to aberrant cell behavior and activation of key signalling pathways to drive phenotypical switching into more mesenchymal-like cancer cells from normal cells [4,7]. Cells are physically connected to the ECM through the transmembrane receptors protein family of integrins focal adhesion (FA-related proteins). External mechanical signals are sensed at FAs and translated into biochemical information through integrin-related signalling pathways for maintaining proper cellular functions in cell shape, migration and survival [8]. Integrin activation is required for the normal functionality of cell adhesion, migration and extracellular matrix assembly. Integrins are a family of heterodimeric proteins comprising alpha and beta subunits that are activated through modulation of the cytoplasmic tail of integrin subunits and this activation is regulated by various biochemical signalling pathways. Besides their requirement for normal cellular mechanosensing, tumor cell migration, invasion, growth and metastasis are also regulated by abbrerant integrin-mediated mechanical signals [9,10]. One of the most extensively studied set of oncogenes of recent times and a potent mechanosensor in mammals are Yes-associated protein (YAP) and its homologous protein Transcriptional Co-Activator With PDZ-Binding Motif (TAZ). YAP/TAZ are sensors of structural and mechanical features of the cell microenvironment that are regulated by soluble extracellular factors, cell-to-cell adhesion and mechanotransduction [11,12] and play a central role in delivering mechanical cues from surrounding cells to the transcriptional machinery of the nucleus [13,14]. YAP and TAZ function as transcriptional co-activators shuttling between the cytoplasm and nucleus to induce the expression of cell-proliferative and anti-apoptotic genes by interacting with transcription factors, especially the TEA domain family members (TEAD) [12]. Although YAP is cytoplasmic at high cell density, the loss of cell contact with neighbouring cells or cell spreading results in YAP translocation to the nucleus. The expansion of cell contacts spreading over their basal substrate, the strength of the substrate and resulting mechanical tension are the key determinants of subcellular YAP localization in response to cell density [11,15,16]. Mechanotransduction affects YAP both independently of the canonical Hippo signalling pathway and with the involvement of key Hippo signalling pathway kinases MST and LATS. Signalling cascades downstream of integrins are known to regulate YAP and TAZ activation [17–19]. Most of the main mechanosensitive phenotypes induced through YAP/TAZ lean on integrin-mediated adhesion [11]. YAP and TAZ can also be directly regulated by the extracellular matrix (ECM) stiffness and YAP itself is involved in FA assembly [15,20,21] (Figure1). Mechanosensing the alterations of ECM stiffness can also be a causal input driving aberrant cell behaviours. The stiffness of ECM is a universal mechanical cue which control’s the preference of a cell between its choice of proliferation and death [16]. When cells perceive stiffness in the ECM, they change their spread and migration potential accordingly. YAP/TAZ activity is also regulated in this scenario. As mentioned, YAP and TAZ are activated by a stiff ECM and stretched cell shape in contrast to inhibition by a soft ECM environment and round cell shape [11,14,16,22,23]. Cells cultured on highly stiff ECM display activated YAP/TAZ with high nuclear localization and subsequent transcriptional activity, whereas cells arrest when YAP/TAZ is inhibited and relocalised to the cytoplasm on a soft ECM. In stiffer ECM, cells continue to proliferate and execute invasive phenotypes by increasing the expression and activity of adhesion receptors and thereby mechanotransduction pathways [11,14–16]. Another key regulator of mechanotransduction in relation to its environment is cellular polarity, which we will discuss in the next section. Cells 2020, 9, 151 3 of 17 Cells 2020, 8, x 3 of 17 FigureFigure 1. The 1. The regulation regulation ofof YAP at at the the level level of the of extrace the extracellularllular matrix involves matrix various involves proteins various involved proteins involvedin stabilizing in stabilizing and activating and activating YAP. In YAP.tegrins Integrins sense the sense external the externalforces an forcesd transmit and this transmit signal thisto talin signal to talin familyfamily membersmembers which which allow allow YAP YAP and and accessory accessory proteins proteins to act toas mechanosensors act as mechanosensors within the within cell. the cell. 2. Mechanotranduction2. Mechanotranduction and and Cell Cell Polarity Polarity Cell polarizationCell polarization is an essentialis an essential function function of several of several cell types cell types including including epithelial epithelial cells cells and migratoryand cells. Thismigratory part ofcells. the This review part willof the focus review on thewill interplay focus on betweenthe interplay cell polaritybetween cell and polarity mechanical and cues. mechanical cues. Cell polarity can occur along several axes, including an anterio-posterior (A–P) axis Cell polarity can occur along several axes, including an anterio-posterior (A–P) axis (e.g., in migratory (e.g., in migratory cells and neurons), and apicobasal and planar axes (e.g., in epithelia). In epithelia cells andand neurons),other cell types, and apico-basal apicobasal polarity and planar is the consequence axes (e.g., inof epithelia).localization and In epitheliaactivity of andmutually other cell types,antagonizing apico-basal complexes, polarity is including the consequence the Par, Crumbs of localization and Scribble and complexes activity (for of
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